EP3349793B1 - Anti-s100a8 pour le traitement de la leucémie - Google Patents

Anti-s100a8 pour le traitement de la leucémie Download PDF

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EP3349793B1
EP3349793B1 EP16845421.3A EP16845421A EP3349793B1 EP 3349793 B1 EP3349793 B1 EP 3349793B1 EP 16845421 A EP16845421 A EP 16845421A EP 3349793 B1 EP3349793 B1 EP 3349793B1
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leukemia
antibody
cells
mice
variable region
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EP3349793A4 (fr
EP3349793A1 (fr
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Philippe Tessier
Malika LAOUEDJ
Frédéric BARABE
Natalie Page
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Universite Laval
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine

Definitions

  • the present description relates to an anti-S1008 protein for treating leukemia.
  • Acute leukemias are the result of a series of genetic and epigenetic events occurring in a stem or progenitor hematopoietic cell, giving rise to a clonal expansion of progenitors with an impaired capacity to differentiate.
  • the past 20 years have been very fruitful in the identification of recurrent genetic lesions in acute leukemia. Improvement in leukemia-free survival has been mostly due to better risk stratification which allows for adjustment of treatment intensity and also to allogenic hematopoietic stem cell transplantation.
  • drugs used in acute myeloid treatment (AML) are basically the same today as they were 25-30 years ago and prognosis remains poor.
  • WO 2006/005186 A1 discloses the use of an anti-S100A8 antibody for treating leukemia.
  • Barabe et al Myeloid-related protein S100A9 induces cellular differentiation in acute myeloid leukemia through TLR2 and TLR4 preceptors, BLOOD, vol. 126, no 23, 3 December 2015, page 3858, XP05537054 ) discloses that blocking S100A8 antibodies led to a marked delay in leukemia progression.
  • the 5-year survival rate is as low as 55% for children with AML and even worse for adults (30-40%) and elderly (> 65 yo) ( ⁇ 15%). Therefore, novel and innovative approaches need to be explored in order to improve leukemia-free survival of acute leukemia patients.
  • the anti-S100A8 specifically binds to a portion of S100A8 protein.
  • the anti-S100A8 specifically binds to a S100A8/S100A8 homodimer or a S100A8/S100A9 heterodimer.
  • the S100A8 protein is a human S100A8.
  • human S100A8 comprises the amino acid sequence depicted in SEQ ID NO: 1.
  • the anti-S100A8 is monoclonal or polyclonal antibody.
  • the anti-S100A8 is a humanized antibody.
  • the anti-S100A8 antibody comprises an epitope binding fragment selected from the group consisting of: Fv, F(ab'), or F(ab')2.
  • the anti-S100A8 antibody comprises a heavy chain variable region encoded by the nucleotide sequence set forth in SEQ ID NO: 3.
  • the anti-S100A8 antibody comprises a heavy chain variable region consisting of SEQ ID NO: 4.
  • the anti-S100A8 antibody comprises a light chain variable region encoded by the nucleotide sequence set forth in SEQ ID NO: 5.
  • the anti-S100A8 antibody comprises a light chain variable region consisting of SEQ ID NO: 6.
  • the anti-S100A8 is formulated for an injection.
  • the anti-S100A8 is formulated for an administration with a chemotherapeutic agent.
  • the chemotherapeutic agent is at least one of daunorubicin, doxorubicin and cytarabine.
  • the anti-S100A8 is formulated for a simultaneous or separate administration with the chemotherapeutic agent.
  • the anti-S100A8 is formulated for an administration after a chemotherapeutic treatment to a subject.
  • composition comprising the anti-S100A8 as described herein and a carrier.
  • composition described herein is for the treatment of leukemia.
  • the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • CMML chronic myelomonocytic leukemia
  • the composition described herein is for stimulating cell differentiation.
  • composition described herein is for inhibiting cell proliferation.
  • composition described herein is for the treatment of acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • a method of treating leukemia in a subject comprising the step of administering the anti-S100A8 or the composition described herein to the subject.
  • a method of stimulating cell differentiation in a subject comprising the step of administering the anti-S100A8 or the composition described herein to the subject.
  • a method for inhibiting cell proliferation in a subject comprising the step of administering the anti-S100A8 or the composition described herein to the subject.
  • a method of stimulating cell differentiation ex vivo comprising the step of administering the anti-S100A8 or the composition described herein to the subject.
  • a method for inhibiting cell proliferation ex vivo comprising a step of administering the anti-S100A8 or the composition described herein to the subject.
  • the subject is a mammal.
  • the subject is a mouse or a human.
  • composition described herein further comprises a S100A9 peptide or a peptidomimetic thereof.
  • the anti-S100A8 encompassed herein is formulated for an administration with an S100A9 peptide.
  • the S100A9 peptide is human S100A9 protein.
  • the peptide comprises the amino acid sequence set forth in SEQ ID NO: 7.
  • the peptide has at least 60%, at least 70% or at least 80%, at least 90% identical, or at least about 95% identity with SEQ ID NO: 7.
  • the peptide consists of the amino acid sequence set forth in SEQ ID NO: 7.
  • anti-S100A8 being an antibody for treating or preventing leukemia.
  • Leukemia encompassed herein can be acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) chronic myeloid leukemia (CML) and/or chronic myelomonocytic leukemia (CMML).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • CML chronic myeloid leukemia
  • CMML chronic myelomonocytic leukemia
  • the S100 protein family comprises 22 members of small (10 to 14 kDa) acidic calcium-binding proteins named as S100A1, S100A2, and so on, according to the time of their discovery and on the chromosome on which they are found. These intracellular proteins are involved in the control of protein phosphorylation, enzymatic activities, Ca 2+ homeostasis, and intermediate filaments polymerisation. S100A8, S100A9 and S100A12 belong to a subset called myeloid related proteins (MRPs) because they are predominantly expressed in neutrophils (30% of cytoplasmic protein) and monocytes, which derive from myeloid precursors.
  • MRPs myeloid related proteins
  • S100A8 and S100A9 are arranged as noncovalently bonded homodimers.
  • S100A8 and S100A9 form a noncovalent heterodimer called S100A8/A9 or calprotectin, presumed to be involved in the cellular control of calcium concentrations.
  • S100A8 and S100A9 are arranged as non-covalently bonded homodimers.
  • S100A8 and S100A9 also form a noncovalent heterodimer called S100A8/A9 or calprotectin in presence of calcium, and this heterodimer is presumed to be involved in the cellular control of calcium concentrations.
  • calprotectin binds to lipids and activates NADPH oxidase inside neutrophils, at least in part by transferring arachidonic acid to NADPH oxidase.
  • S100A8 and S100A9 are presumed to bind to RAGE, the scavenger receptor (CD36) or the Toll-like receptor 4 (TLR4).
  • Human peptide sequence of S100A8 consists of:
  • Humanization can be necessary when the process of developing a specific antibody involves generation in a non-human immune system (such as that in mice).
  • Antibody humanization methods are designed to produce a molecule with minimal immunogenicity when applied to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • the protein sequences of antibodies produced in this way are partially distinct from homologous antibodies occurring naturally in humans, and are therefore potentially immunogenic when administered to human patients.
  • Humanized antibodies encompassed herein can be produced via enrichment technologies such as phage display or immunization of transgenic mice bearing the antibody human gene repertoire have provided powerful means to generate human antibodies.
  • the antibody described herein specifically binds to an epitope on S100A8.
  • the antibody comprises an epitope binding fragment that is selected from: Fv and/or F(ab') and/or F(ab')2.
  • the antibody comprises an epitope-binding single chain antibody.
  • the antibody encompassed herein comprises a heavy chain variable region encoded by nucleotide sequence:
  • the antibody comprises a heavy chain variable region consisting of:
  • the antibody encompassed herein comprises a light chain variable region encoded by nucleotide sequence:
  • the antibody comprises a light chain variable region consisting of:
  • compositions comprise a therapeutically effective amount of the antibody, and a physiologically or a pharmaceutically acceptable carrier or excipient.
  • a suitable physiological or pharmaceutical carrier includes but is not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the formulation should suit the mode of administration.
  • An antibody as defined herein, acting as inhibitor or antagonist of S100A8 protein, can be administered alone or in combination with other antibodies directed toward other complementary targets, including but not limited to, other S100 polynucleotides or polypeptides.
  • the antibodies encompassed herein may be advantageously utilized in combination with other monoclonal or chimeric antibodies, with cytokines, or with S100 proteins.
  • the antibodies may be administered alone or in combination with other types of treatments.
  • the antibody described herein can be administered in combination, simultaneously or separately, with for example a chemotherapeutic agent, such as daunorubicin (Cerubidine), doxorubicin (Adriamycin), and cytarabine.
  • a chemotherapeutic agent such as daunorubicin (Cerubidine), doxorubicin (Adriamycin), and cytarabine.
  • a chemotherapeutic agent such as daunorubicin (Cerubidine), doxorubicin (Adriamycin), and cytarabine.
  • a chemotherapeutic agent such as daunorubicin (Cerubidine), doxorubicin (Adriamycin), and cy
  • a method for treating leukemia comprising the step of administering to a subject in need thereof an effective amount of the antibody as defined herein or the composition as defined herein.
  • the Cancer Genome Atlas (TCGA) Research Network performed whole genome/whole exome sequencing on 200 adult AML cases along with RNA, microRNA and DNA-methylation analysis.
  • S100A8 and S100A9 were amongst the top 5 discriminatory genes for one important sub-group mainly composed of myelomonocytic and monocytic AML, with high RPKM levels ( Cancer Genome Atlas Research, N., 2013, The New England journal of medicine, 368: 2059-2074 ).
  • High concentrations of S100A8 and S100A9 proteins are found in the serum of patients with acute and chronic myeloid leukemia ( Ivanov et al., 1996, Immunology letters, 49: 7-13 ), and these concentrations correlate with growth-stimulating activity in these sera.
  • S100A8 has been identified as a predictor of poor survival in de novo AML patients ( Nicolas et al., 2011, Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 25: 57-65 ).
  • S100A8/A9 constitutive over-expression of S100A8/A9 is also associated with resistance to prednisone treatment in MLL-rearranged B-ALL, and forced expression of S100A8/A9 in MLL-rearranged B-ALL cells transform prednisone-sensitive into prednisone insensitive cells in vitro ( Spijkers-Hagelstein et al., 2012, Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 26: 1255-1265 ).
  • S100A8 and S100A9 proteins were measured using two well-characterized myeloid leukemia models induced by overexpression of Hoxa9 and the cofactor Meis1 or expression of the oncogene MLL-ENL in hematopoietic progenitors and stem cells (HPSC) transplanted into lethally irradiated recipient.
  • HPSC hematopoietic progenitors and stem cells
  • S100A8/A9 Elevated concentrations of S100A8/A9 were found in bone marrow and spleen supernatants of AML recipient, indicating that extracellular fluids are also enriched in those proteins. S100A8/A9 concentration gradually increased as leukemia progressed and strongly correlated to regress of leukemic cells from the bone marrow to the blood (see Fig. 3 ).
  • H9M driven AML secondary recipients were treated i.p with 10mg/kg of either pAb anti-S100A8 or with mAb anti-S100A9.
  • pAb anti-S100A8 or mAb anti-S100A9 interact with both homodimeric S100A8/A8 or S100A9/A9 respectively, and heterodimeric S100A8/A9.
  • Injection of anti-S100A8 led to a marked delay in leukemia progression and significantly extended survival compared to control immunoglobulins ( Fig. 4 ). This was associated with reduced weight loss and improvement of the behavior of leukemic mice in anti-S100A8-treated mice ( Fig. 5 ).
  • S100A8 promotes AML pathogenesis by interfering with myeloid cell differentiation.
  • anti-S100A8 human cord blood cells transfected with the fusion gene MLL-AF9 were stimulated with anti-S100A8 for 72h.
  • Cell differentiation was examined using expression of CD14 as a marker of cell differentiation.
  • Anti-S100A8 mAb 1F8 doubled the number of cells expressing of CD14 ( Fig 10A ), suggesting a stimulation of cell differentiation.
  • anti-S100A8 mAb 1F8 increased the number of cells in G0/G1 and S phases ( Fig 10B ), indicating an inhibition of proliferation of the cells.
  • the anti-S100A8 antibody encompassed herein can be administered with a S100A9 peptide in order to significantly increase the delay in leukemia progression and extended survival compared to control immunoglobulins or compared to administration of the anti-S100A8 antibody or S100A9 peptide alone.
  • S100A9 also known as calgranulin B and myeloid related protein-14 (MRP-14), is a calcium- and zinc-binding protein that belongs to the S100 protein family.
  • S100A9 is highly expressed by the myeloid cell lineage and is found in the extracellular milieu during inflammatory conditions. S100A9 forms heterodimers with S100A8, another member of the S100 family. However, S100A9 may also form monomers which execute specific functions.
  • Human S100A9 has a molecular mass of about 13 kDa and is composed of 114 amino acid residues.
  • composition comprising an anti-S100A8 antibody and a S100A9 peptide.
  • composition comprising an anti-S100A8 antibody comprising a heavy chain variable region encoded by the nucleotide sequence set forth in SEQ ID NO: 3 or 4, a light chain variable region encoded by the nucleotide sequence set forth in SEQ ID NO: 5 or 6, and a S100A9 peptide comprising the amino acid sequence set forth in SEQ ID NO: 7 for treating leukemia.
  • injection of anti-S100A8 protects from AML by promoting the differentiation of leukemia cells, resulting in reduced proliferation.
  • mice Primary leukemia recipient C57BL/6 mice were irradiated (7 Gy), then injected i.v. 24 h later with 4 x 10 5 infected bone marrow cells (expressing Hoxa9, Meis1 and Egfp). Mice were followed every day for signs of leukemia. Peripheral blood was harvested every week to quantify the number of leukemia cells (expressing GFP) by flow cytometry. Moribund mice were sacrificed and the peripheral blood and bone marrow were harvested.
  • Secondary leukemia were induced by injecting 2 x 10 5 bone marrow cells from primary leukemia mice into sublethally irradiated (4Gy) recipient.
  • Leukemic cells isolated from bone marrow of primary leukemia mice were injected into sublethally irradiated (4Gy) recipient C57BL/6 mice.
  • the presence of AML cells (EGFP+) in peripheral blood was evaluated by flow cytometry 14 days later.
  • Mice were injected i.p three times per week with 100 ⁇ g purified rabbit IgG anti-S100A8 starting on day 3. Mice exhibiting signs of ill health were sacrificed and peripheral blood and bone marrow were harvested for histology and flow cytometry analyses.
  • Human cord blood cells transfected with the fusion gene MLL-AF9 were cultivated in IMDM supplemented with 15% fetal calf serum, IL-6 and stem cell factor.
  • the cells were plated 96 well microtiter plates (200 000 cells/well), then stimulated with 20 ⁇ g/ml of mAb 1F8 anti-S100A8, or PBS. After 72h, cells were collected and immunophenotyping was performed by flow cytometry following staining with anti-CD14. Cell cycle was analyzed by propidium iodide staining.
  • Leukemic cells isolated from bone marrow of primary leukemia mice were injected into sublethally irradiated (4Gy) recipient C57BL/6 mice.
  • the presence of AML cells (EGFP+) in peripheral blood was evaluated by flow cytometry 14 days later.
  • Mice were injected i.p three times per week with 100 ⁇ g purified rabbit IgG anti-S100A8, 20 ⁇ g of recombinant mouse S100A9 protein, or a combination of anti-S100A8 and S100A9 protein starting on day 3.
  • Mice exhibiting signs of ill health were sacrificed and peripheral blood and bone marrow were harvested for histology and flow cytometry analyses.

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Claims (10)

  1. Anticorps anti-S100A8 comprenant une région variable de chaîne lourde constituée de SEQ ID N° : 4, et une région variable de chaîne légère constituée de SEQ ID N° : 6.
  2. Anticorps anti-S100A8 selon la revendication 1, comprenant une région variable de chaîne lourde codée par la séquence nucléotidique présentée dans SEQ ID N° : 3 et une région variable de chaîne légère codée par la séquence nucléotidique présentée dans SEQ ID N° : 5.
  3. Anticorps anti-S100A8 selon la revendication 1 ou 2, dans lequel ledit anti-S100A8 se lie spécifiquement à un homodimère S100A8 / S100A8 ou à un hétérodimère S100A8 / S100A9.
  4. Anticorps anti-S100A8 selon l'une quelconque des revendications 1 à 3, dans lequel ledit anti-S100A8 est un anticorps humanisé.
  5. Anticorps anti-S100A8 destiné à être utilisé dans le traitement de la leucémie, ledit anticorps anti-S100A8 étant l'anticorps anti-S100A8 défini dans l'une quelconque des revendications 1 à 4.
  6. Composition comprenant un anticorps anti-S100A8 selon l'une quelconque des revendications 1 à 4 et un support.
  7. Composition selon la revendication 6, destinée à être utilisée dans le traitement de la leucémie.
  8. Composition destinée à être utilisée selon la revendication 7, dans laquelle ladite leucémie est la leucémie lymphoblastique aiguë (LLA), la leucémie myéloïde aiguë (LMA), la leucémie lymphoïde chronique (LLC), la leucémie myéloïde chronique (LMC) et la leucémie myélomonocytaire chronique (LMMC).
  9. Composition selon la revendication 6, comprenant en outre un peptide S100A9 ou un peptidomimétique de celui-ci.
  10. Composition selon la revendication 9, dans laquelle le peptide S100A9 est la protéine S100A9 humaine.
EP16845421.3A 2015-09-14 2016-09-13 Anti-s100a8 pour le traitement de la leucémie Active EP3349793B1 (fr)

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PCT/CA2016/051078 WO2017045070A1 (fr) 2015-09-14 2016-09-13 Anti-s100a8 pour le traitement de la leucémie

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WO2019010566A1 (fr) * 2017-07-10 2019-01-17 UNIVERSITé LAVAL Anti-s100a8/a9 pour inhiber l'activité immunosuppressive de cellules mdsc
CN112040982A (zh) * 2018-04-27 2020-12-04 国立大学法人冈山大学 抗s100a8/a9抗体及其用途
WO2020051460A1 (fr) * 2018-09-07 2020-03-12 Sanford Burnham Prebys Medical Discovery Institute Méthodes de diagnostic et de traitement de la maladie inflammatoire chronique de l'intestin
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Title
TAKADA Y ET AL: "Identification of a regulatory region of integrin beta 1 subunit using activating and inhibiting antibodies.", THE JOURNAL OF BIOLOGICAL CHEMISTRY 15 AUG 1993, vol. 268, no. 23, 15 August 1993 (1993-08-15), pages 17597 - 17601, ISSN: 0021-9258 *

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CA2998410A1 (fr) 2017-03-23
US10894082B2 (en) 2021-01-19
JP2018527410A (ja) 2018-09-20
WO2017045070A1 (fr) 2017-03-23
JP6750018B2 (ja) 2020-09-02
EP3349793A4 (fr) 2019-05-01
CN108367068B (zh) 2021-08-03
EA038980B1 (ru) 2021-11-17
EA201890739A1 (ru) 2018-09-28
US20180256710A1 (en) 2018-09-13
HK1250649A1 (zh) 2019-01-11
EP3349793A1 (fr) 2018-07-25

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